Compounds which have the property of inhibiting the action of metalloproteinases involved in connective tissue breakdown such as collagenase, stromelysin and gelatinase (known as "matrix metalloproteinases", and herein referred to as MMPs) are thought to be potentially useful for the treatment or prophylaxis of conditions involving such tissue breakdown, for example rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal epidermal or gastric ulceration, and tumour metastasis, invasion and growth. MMP inhibitors are also of potential value in the treatment of neuroinflammatory disorders, including those involving myelin degradation, for example multiple sclerosis. as well as in the management of angiogenesis dependent diseases, which include arthritic conditions and solid tumour growth as well as psoriasis, proliferative retinopathies, neovascular glaucoma ocular tumours, angiofibromas and hemangiomas. However, the relative contributions of individual MMPs in any of the above disease states is not yet fully understood.
Metalloproteinases are characterised by the presence in the structure of a zinc(II) ionic site at the active site. It is now known that there exists a range of metalloproteinase enzymes that includes fibroblast collagenase (Type 1), PMN-collagenase, 72 kDa-gelatinase, 92 kDa-gelatinase, stromelysin, stromelysin-2 and PUMP-1 (J. F. Woessner, FASEB J, 1991, 5, 2145-2154). Many known MMP inhibitors are peptide derivatives, based on naturally occuring amino acids, and are analogues of the cleavage site in the collagen molecule. Chapman et al. (J. Med. Chem. 1993, 36, 4293-4301) report some general structure/activity findings in a series of N-carboxyalkyl peptides. Other known MMP inhibitors are less peptidic in structure, and may more properly be viewed as pseudopeptides or peptide mimetics. Such compounds usually have a functional group capable of binding to the zinc (II) site in the MMP, and known classes include those in which the zinc binding group is a hydroxamic acid, carboxylic acid, sulphydryl, and oxygenated phosphorus (eg phosphinic acid and phosphonamidate including aminophosphonic acid) groups.
Three known classes of pseudopeptide or peptide mimetic MMP inhibitors have a hydroxamic acid group, N-formyl-N-hydroxyamino or a carboxylic group respectively as their zinc binding groups. With a few exceptions, such known MMPs may be represented by the structural formula (I) ##STR2##
in which X is the zinc binding hydroxamic acid (--CONHOH), N-formyl-N-hydroxyamino (--NH(OH)CHO) or carboxylic acid (--COOH) group and the groups R.sub.1 to R.sub.5 are variable in accordance with the specific prior art disclosures of such compounds. Examples of patent publications disclosing such structures are given below.
In such compounds, it is generally understood in the art that variation of the zinc binding group and the substituents R.sub.1, R.sub.2 and R.sub.3 can have an appreciable effect on the relative inhibition of the metalloproteinase enzymes. The group X interacts with metalloproteinase enzymes by binding to a zinc(II) ion in the active site. Generally the hydroxamic acid group is preferred over the carboxylic acid group in terms of inhibitory activity against the various metalloproteinase enzymes. However, the carboxylic acid group in combination with other substituents can provide selective inhibition of gelatinase (EP-489.577-A). The R.sub.1, R.sub.2 and R.sub.3 groups are believed to occupy respectively the P1, P1' and P2' amino acid side chain binding sites for the natural enzyme substrate. There is evidence that a larger R.sub.1 substituent can enhance activity against stromelysin, and that a (C.sub.1 -C.sub.6)alkyl group (such as isobutyl) at R.sub.2 may be preferred for activity against collagenase whilst a phenylalkyl group (such as phenylpropyl) at R.sub.2 may provide selectivity for gelatinase over the other metalloproteinases.
Tumour necrosis factor (herein referred to as "TNF") is a cytokine which is produced initially as a cell-associated 28 kD precursor. It is released as an active, 17 kD form, which can mediate a large number of deleterious effects in vivo. When administered to animals or humans it causes inflammation, fever, cardiovascular effects, haemorrhage, coagulation and acute phase responses, similar to those seen during acute infections and shock states. Chronic administration can also cause cachexia and anorexia. Accumulation of excessive TNF can be lethal.
There is considerable evidence from animal model studies that blocking the effects of TNF with specific antibodies can be beneficial in acute infections, shock states, graft versus host reactions and autoimmune disease. TNF is also an autocrine growth factor for some myelomas and lymphomas and can act to inhibit normal haematopoiesis in patients with these tumours.
Compounds which inhibit the production or action of TNF are therefore thought to be potentially useful for the treatment or prophylaxis of many inflammatory, infectious, immunological or malignant diseases. These include, but are not restricted to, septic shock, haemodynamic shock and sepsis syndrome, post ischaemic reperfusion injury, malaria, Crohn's disease, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic disease, cachexia, graft rejection, cancer, autoimmune disease, AIDS, rheumatoid arthritis, multiple sclerosis, radiation damage, toxicity following administration of immunosuppressive monoclonal antibodies such as OKT3 or CAMPATH-1 and hyperoxic alveolar injury.
Since excessive TNF production has been noted in several diseases or conditions also characterised by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF production may have particular advantages in the treatment or prophylaxis of diseases or conditions in which both mechanisms are involved.
As mentioned above MMP inhibitors have been proposed with hydroxamic acid, N-formyl-N-hydroxyamino or carboxylic acid zinc binding groups. The following patent publications disclose such MMP inhibitors:
U.S. Pat. No. 4,599,361 (Searle) PA1 EP-A-2321081 (ICI) PA1 EP-A-0236872 (Roche) PA1 EP-A-0274453 (Bellon) PA1 WO 90/05716 (British Biotech) PA1 WO 90/05719 (British Biotech) PA1 WO 91/02716 (British Biotech) PA1 WO 92/09563 (Glycomed) PA1 U.S. Pat. No. 5,183,900 (Glycomed) PA1 U.S. Pat. No. 5,270,326 (Glycomed) PA1 WO 92/17460 (SB) PA1 EP-A-0489577 (Celltech) PA1 EP-A-0489579 (Celltech) PA1 EP-A-0497192 (Roche) PA1 U.S. Pat. No. 5,256,657 (Sterling) PA1 WO 92/13831 (British Biotech) PA1 WO 92/22523 (Research Corp) PA1 WO 93/09090 (Yamanouchi) PA1 WO 93/09097 (Sankyo) PA1 WO 93/20047 (British Biotech) PA1 WO 93/24449 (Celltech) PA1 WO 93/24475 (Celltech) PA1 EP-A-0574758 (Roche) PA1 EP-A-0575844 (Roche) PA1 WO 94/02446 (British Biotech) PA1 WO 94/02447 (British Biotech) PA1 WO 94/21612 (Otsuka) PA1 WO 94/21625 (British Biotech) PA1 WO 94/24140 (British Biotech) PA1 WO 94/25434 (Celltech) PA1 WO 94/25435 (Celltech PA1 WO 95/04033 (Celltech) PA1 WO 95/04735 (Syntex) PA1 WO 95/04715 (Kanebo) PA1 WO 95/06031 (Immunex) PA1 WO 95/09841 (British Biotech) PA1 WO 95/12603 (Syntex) PA1 WO 95/19956 (British Biotech) PA1 WO 95/19957 (British Biotech) PA1 WO 95/19961 (British Biotech) PA1 WO 95/19965 (Glycomed) PA1 WO 95/22966 (Sanofi Winthrop) PA1 WO 95/23790 (SB) PA1 X is a --CO.sub.2 H, --NH(OH)CHO or --CONHOH group; PA1 R.sub.1 is a cycloalkyl, cycloalkenyl or non-aromatic heterocyclic ring containing up to 3 heteroatoms, any of which may be (i) substituted by one or more substituents selected from C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, halo, cyano (--CN), --CO.sub.2 H, --CO.sub.2 R, --CONH.sub.2, --CONHR, --CON(R).sub.2, --OH, --OR, oxo-, --SH, --SR, --NHCOR, and --NHCO.sub.2 R wherein R is C.sub.1 -C.sub.6 alkyl or benzyl and/or (ii) fused to a cycloalkyl or heterocyclic ring; PA1 R.sub.2 is a C.sub.1 -C.sub.2 alkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, phenyl(C.sub.1 -C.sub.6 alkyl)-, heteroaryl(C.sub.1 -C.sub.6 alkyl)-, cycloalkyl(C.sub.1 -C.sub.6 alkyl)-, cycloalkenyl(C.sub.1 -C.sub.6 alkyl)-, phenoxy(C.sub.1 -C.sub.6 alkyl)-, heteroaryloxy(C.sub.1 -C.sub.6 alkyl)-, phenyl(C.sub.1 -C.sub.6 alkyl)O(C.sub.1 -C.sub.6 alkyl)-, heteroaryl(C.sub.1 -C.sub.6 alkyl)O(C.sub.1 -C.sub.6 alkyl)-, phenyl(C.sub.1 -C.sub.6 alkyl)S(C.sub.1 -C.sub.6 alkyl)-, or heteroaryl(C.sub.1 -C.sub.6 alkyl)S(C.sub.1 -C.sub.6 alkyl)- group, any one of which may be optionally substituted by C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, halo, cyano (--CN), phenyl, substituted phenyl or heteroaryl; PA1 R.sub.3 is the characterising group of a natural or non-natural a amino acid in which any functional groups may be protected; PA1 R.sub.4 is (a) an optionally substituted cycloalkyl or cycloalkenyl ring or PA1 R.sub.5 is hydrogen or a C.sub.1 -C.sub.6 alkyl group; PA1 or a salt, hydrate or solvate thereof. PA1 C atom carrying the R.sub.1 and X groups --S, PA1 C atom carrying the R.sub.2 group --R, PA1 C atom carrying the R.sub.3 group --S, but mixtures in which the above configurations predominate are also contemplated. PA1 R.sub.2 may for example be C.sub.1 -C.sub.12 alkyl, C.sub.3 -C.sub.6 alkenyl, phenyl(C.sub.1 -C.sub.6 alkyl)- or phenoxy(C.sub.1 -C.sub.6 alkyl) optionally substituted in the phenyl ring by halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy or phenyl. Specific examples of such groups include iso-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, phenylpropyl, 4-chlorophenylpropyl, 4-methylphenylpropyl, 4-methoxyphenylpropyl, 4-phenyl-phenylpropyl and phenoxybutyl. Presently preferred are compounds in which R.sub.2 is iso-butyl, n-octyl, benzyloxypropyl, phenoxybutyl or 4-phenyl-phenylpropyl. PA1 R.sub.3 may for example be C.sub.1 -C.sub.6 alkyl, benzyl, 2,- 3-, or 4-hydroxybenzyl, 2,- 3-, or 4-benzyloxybenzyl, 2,- 3-, or 4-C.sub.1 -C.sub.6 alkoxybenzyl, or benzyloxy(C.sub.1 -C.sub.6 alkyl)- group; or PA1 the characterising group of a natural .alpha. amino acid in which any functional group may be protected, any amino group may be acylated and any carboxyl group present may be amidated; or PA1 a group -[Alk].sub.n R.sub.5 where Alk is a (C.sub.1 -C.sub.6)alkyl or (C.sub.2 -C.sub.6)alkenyl group optionally interrupted by one or more --O--, or --S-- atoms or --N(R.sub.7)-- groups [where R.sub.7 is a hydrogen atom or a (C.sub.1 -C.sub.6)alkyl group], n is 0 or 1, and R.sub.6 is an optionally substituted cycloalkyl or cycloalkenyl group; or PA1 a benzyl group substituted in the phenyl ring by a group of formula --OCH.sub.2 COR.sub.8 where R.sub.8 is hydroxyl, amino, (C.sub.1 -C.sub.6)alkoxy, phenyl(C.sub.1 -C.sub.6)alkoxy, (C.sub.1 -C.sub.6)alkylamino, di((C.sub.1 -C.sub.6)alkyl)amino, phenyl(C.sub.1 -C.sub.6)alkylamino, the residue of an amino acid or acid halide, ester or amide derivative thereof, said residue being linked via an amide bond, said amino acid being selected from glycine, .alpha. or .beta. alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, and aspartic acid; or PA1 a heterocyclic(C.sub.1 -C.sub.6)alkyl group, either being unsubstituted or mono- or di- substituted in the heterocyclic ring with halo, nitro, carboxy, (C.sub.1 -C.sub.6)alkoxy, cyano, (C.sub.1 -C.sub.6)alkanoyl, trifluoromethyl (C.sub.1 -C.sub.6)alkyl, hydroxy, formyl, amino, (C.sub.1 -C.sub.6)alkylamino, di-(C.sub.1 -C.sub.6)alkylamino, mercapto, (C.sub.1 -C.sub.6)alkylthio, hydroxy(C.sub.1 -C.sub.6)alkyl, mercapto(C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkylphenylmethyl; or PA1 a group --CR.sub.a R.sub.b R.sub.c in which: PA1 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl cycloheptyl, cyclooctyl or adamantyl; PA1 optionally substituted phenyl, napthyl, furanyl, thienyl, pyrrolinyl, tetrahydrofuranyl, imidazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyridinyl N-oxides, piperazinyl, indolyl, benzimidazolyl, benzotriazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, dithianyl, benzo[b]thienyl, isoxazolyl or quinolinyl. Examples of particular R.sub.4 groups of this type include phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethyl, 2-t-butylphenyl, 3-t-butylphenyl, 4-t-butylphenyl, 4-t-butyl-2,6dimethylphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-acetylphenyl, 3-acetylphenyl, 4-acetylphenyl, 2-methylsulphonylphenyl, 3-methylsulphonylphenyl, 4-methylsulphonylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-ditrifluoromethylphenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-N,N-dimethylaminophenyl, 3-N,N-dimethylaminophenyl, 4-N,N-dimethylaminophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-napthyl, furan-2-yl, thien-2-yl, pyrrol-2-yl, tetrahydrofuran-2-yl, imidazol-2-yl, thiazol-2-yl, 4-ethoxycarbonylmethylthiazol-2-yl, 4-phenylthiazol-2-yl, 4,5-dimethylthiazol-2-yl, 5-bromothiazol-2-yl, 4-tert-butylthiazol-2-yl, benzothiazol-2-yl, 1,2,4-oxadiazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 3-phenyl-1,2,4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-thiadiazol-5-yl, 3-phenyl-1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, N-oxides of pyridin-2-yl pyridin-3-yl and pyridin-4-yl, piperazin-1-yl, indol-2-yl, benzimidazol-2-yl, benzotriazol-2-yl, pyrazin-2-yl, 1,2-pyridazin-3-yl, 1,3-pyrimidin-5-yl, 1,3-dithian-2-yl, benzo[b]thien-2-yl, isoxazol-5-yl, quinolin-3-yl. Presently preferred are compounds in which R.sub.4 is phenyl, 3-methoxyphenyl, pyridin-2-yl, pyridin-3-yl, and thiazol-2-yl, 4,5-dimethylthiazol-2-yl, 5-bromothiazol-2-yl, 4-ethoxycarbonylmethylthiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl or 4-tertbutylthiazol-2-yl. Particularly preferred R.sub.4 groups of this type are 3-methoxyphenyl, pyridin-2-yl, pyridin-3-yl, thiazol-2-yl, 4-ethoxycarbonylmethylthiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl or 4-tert-butylthiazol-2-yl; PA1 a group --CHR.sup.x R.sup.y wherein R.sup.x and R.sup.y independently represent optionally substituted phenyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinolyl, pyrimidinyl, piperazinyl or triazinyl. Examples of particular R.sup.x and R.sup.y include phenyl and 4-chlorophenyl. Where R.sup.x and R.sup.y are linked covalently, an example of a group R.sub.4 is 9-H-fluoren-9-yl; PA1 a polyether chain possessing at least two non-adjacent oxygen atoms, for example 2-(2-methoxyethoxymethoxy)ethyl, 1,1-dimethyl-2-(2-methoxyethoxymethoxy)ethyl, 2-(2-ethoxyethoxymethoxy)ethyl, 2-(2-(2-methoxyethoxy)ethoxy)ethyl, 2-(2-(3-methoxypropoxymethoxy)ethyl, 3-(2-methoxyethoxymethoxy)propyl, 2,2-dimethyl-3-(2-methoxyethoxymethoxy)propyl, 2-(2-methoxyethoxy)ethyl, 3-(2-methoxyethoxy)propyl, 2-methyl-2,2-di(2-methoxyethyl)propyl, 2-methyl-2,2-di(2-methoxyethyl)butyl, and 2-methyl-2,2-di(2-methoxymethyl)propyl. A presently preferred R.sub.4 group of this type is 2-(2-methoxyethoxy)ethyl; PA1 hydrogen, methyl, ethyl, n- or iso-propyl, n-, sec- or tert-butyl, hydroxyethyl, hydroxypropyl, 2,2-dimethyl-3-hydroxypropyl, hydroxybutyl, methoxyethyl, ethoxyethyl, methoxypropyl, 2,2-dimethyl-3-methoxypropyl, 2,2-dimethyl-3-ethoxypropyl, 2-ethylthioethyl, 2-acetoxyethyl, N-acetyl-aminoethyl, 3-(2-pyrrolidone)propyl, optionally substituted phenylethyl eg 2-phenyl-2-methyleth-2-yl, phenylpropyl, phenylbutyl, or phenylpentyl. Presently preferred R.sub.4 groups of this type are hydrogen or methyl. PA1 (i) a method of management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by MMPs and/or TNF in mammals, in particular in humans, which method comprises administering to the mammal an effective amount of a compound as defined with respect to formula (I) above, or a pharmaceutically acceptable salt thereof; and PA1 (ii) a compound as defined with respect to formula (I) for use in human or veterinary medicine, particularly in the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by MMPs and/or TNF; and PA1 (iii) the use of a compound as defined with respect to formula (I) in the preparation of an agent for the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by MMPs and/or TNF. PA1 DIPE Diisopropyl ether PA1 DMAP 4-Dimethyl-aminopyridine PA1 DMF N,N-Dimethylformamide PA1 EDC N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride PA1 HOBt 1-Hydroxybenzotriazole PA1 NMR Nuclear magnetic resonance PA1 NMM N-methylmorpholine PA1 NaHMDS Sodium bis(trimethylsilyl)amide PA1 TESCI Chlorotriethylsilane PA1 TFA Trifluoroacetic acid PA1 THF Tetrahydrofuran PA1 TLC Thin layer chromatography